Description:
Donor lymphocyte infusion (DLI), also called donor leukocyte or buffy-coat infusion, is a type of therapy in which T lymphocytes from the blood of a donor are given to a patient who has already received a hematopoietic cell transplant (HCT) from the same donor. The DLI therapeutic effect results from a graft-versus-leukemic or graft-versus-tumor effect due to recognition of certain antigens on the cancer cells by the donor lymphocytes and the resultant elimination of the tumor cells.

For individuals who have had an allogeneic HCT who receive DLI, the evidence includes nonrandomized comparative studies and case series. Relevant outcomes are overall survival and change in disease status. In various hematologic malignancies and for various indications such as planned or preemptive DLI, treatment of relapse or conversion of mixed to full donor chimerism, patients have shown evidence of responding to DLI. Response rates to DLI for relapsed hematologic malignancies following an allogeneic HCT are best in chronic myelogenous leukemia (CML), followed by the lymphomas, multiple myeloma and acute leukemias, respectively. Other than CML, clinical responses are most effective when chemotherapy induction is used to reduce the tumor burden before DLI. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. 

For individuals who have had an allogeneic HCT who receive a modified (genetic or other ex vivo modification) donor lymphocytes infusion, the evidence includes case series. Relevant outcomes are overall survival and change in disease status. The case series have demonstrated the feasibility of the technique and no serious adverse effects. Without a comparison to standard treatment, the efficacy of administering modified donor lymphocytes is unknown. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background 
Approximately 40% to 60% of patients who receive a donor lymphocyte infusion (DLI) develop graft-versus-host disease (GVHD), and the development of GVHD predicts a response to the DLI. Treatment-related mortality after DLI is 5% to 20%. There does not seem to be a correlation between the type of hematologic malignancy for which the DLI is given and the development of GVHD.¹ The risk of developing GVHD is related, in part, to DLI dose and therapy before DLI.

DLI may be used for various indications such as relapse after allogeneic hematopoietic cell transplantation (HCT), to prevent disease relapse in the setting of T cell‒depleted grafts or nonmyeloablative conditioning regimens or to convert mixed to full donor chimerism. Management of relapse, which occurs in approximately 40% of all hematologic malignancy patients, is the most common indication for DLI.²

The literature is heterogeneous when reporting methods of cell collection, indication (e.g., planned after chemotherapy, in early relapse), cell dose infused and cell subtype used.¹ In addition, many studies include multiple diseases with little information on disease-specific outcomes; however, DLI is used in nearly all hematologic malignancies for which allogeneic HCT is performed, including chronic myeloid leukemia, acute myeloid and lymphoblastic leukemias, myelodysplastic syndromes, multiple myeloma and Hodgkin and non-Hodgkin lymphoma.

Regulatory Status
The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

Policy: 
Donor lymphocyte infusion may be considered MEDICALLY NECESSARY following allogeneic hematopoietic cell transplantation (HCT) that was originally considered medically necessary for the treatment of a hematologic malignancy that has relapsed or is refractory, to prevent relapse in the setting of a high risk of relapse (see Policy Guidelines section) or to convert a patient from mixed to full donor chimerism.

Donor lymphocyte infusion is considered investigational and/or unproven and therefore is consdered NOT MEDICALLY NECESSARY following allogeneic HCT that was originally considered investigational for the treatment of a hematologic malignancy.

Donor lymphocyte infusion is considered invetigational and/or unproven and therefore is considered NOT MEDICALLY NECESSARY as a treatment of nonhematologic malignancies following a prior allogeneic HCT.

Genetic or other modification of donor lymphocytes is considered investigational and/or unproven and therefore is considered NOT MEDICALLY NECESSARY.

Policy Guidelines 
Settings considered high risk for relapse include T cell‒depleted grafts or nonmyeloablative (reduced-intensity conditioning) allogeneic hematopoietic cell transplantation.

CPT code 38242 describes allogeneic donor lymphocyte infusions.

Benefit Application
BlueCard/National Account Issues 
Charges for the leukapheresis procedure for the donor should be considered as recipient expenses, and the claim be used following allogeneic hematopoietic cell transplantation (HCT) that is considered investigational, such as following allogeneic HCT for multiple myeloma. The policy statement considers donor lymphocyte infusion use in this case investigational. Plan contracts should be reviewed when considering the medical necessity of services that are used with an intervention considered investigational. 

Rationale
This evidence review was originally created in January 1998 and has been updated regularly with searches of the MEDLINE database. The most recent literature review was performed for the period of April 2, 2015 through Dec. 15, 2015.

Several review articles have summarized studies reporting the use of donor lymphocyte infusion (DLI) for the treatment of patients with hematologic malignancies that relapse following allogeneic hematopoietic cell transplantation (HCT).^1,2,3  

Donor Lymphocyte Infusion
Chronic Myelogenous Leukemia
DLI has been most effective in chronic myelogenous leukemia (CML), inducing a molecular complete remission (CR) in up to 80% of patients who relapse in chronic phase. Only a 12% to 33% response rate has been reported in patients in accelerated or blast phase. Response duration to DLI in patients with relapsed CML after HCT is long-standing in most patients. 

Several large series have reported outcomes of patients with relapsed CML after receiving DLI.^4,5,6,7,8,9 These studies comprise more than 1,000 patients, approximately half of whom had only molecular or cytogenetic relapse at the time of DLI.¹ The cell doses varied among patients, with some receiving multiple DLI infusions and others, planned dose escalations. Despite these variations, a molecular or cytogenetic CR was achieved in 74% (746/1007) of patients. Overall survival (OS) at 3 years or more ranged from 53% to 95%,² was 64% at 5 years and was 59% at 10 years after DLI in another series.⁹  

The role of DLI in CML has changed since the introduction of tyrosine kinase inhibitors (TKIs) in CML treatment, which keeps the disease under control instead of proceeding to HCT. However, for patients who develop resistance to TKIs or are unable to tolerate their adverse effects, HCT and DLI may be a disease management option. 

Acute Leukemias, Myelodysplasia and Other Myeloproliferative Diseases
In a 2013 systematic review, El-Jurdi et al. evaluated 39 prospective and retrospective studies using DLI to treat relapse after HCT for lymphoid malignancies, including acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), multiple myeloma, non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL).¹⁰ No randomized controlled trials were identified. Studies selected were heterogeneous, thus limiting interpretation of the review. Reported pooled proportions of CR (95% confidence interval [CI]) were 27% (16% to 40%) for ALL, 55% (15% to 92%) for CLL, 26% (19% to 33%) for multiple myeloma, 52% (33% to 71%) for NHL and 37% (20% to 56%) for HL.  

An observational study compared different treatments for 147 consecutive patients who relapsed after allogeneic HCT for myelodysplastic syndrome.¹¹ Sixty-two patients received HCT or DLI, 39 received cytoreductive treatment and 46 were managed with palliative or supportive care. Two-year OS rates were 32%, 6% and 2%, respectively (p < .001). In multivariate analysis, 4 factors adversely influenced 2-year OS rates: history of acute graft-versus-host disease (GVHD; hazard ratio [HR], 1.83; 95% CI, 1.26 to 2.67; p = 0.002), relapse within 6 months (HR = 2.69; 95% CI, 0.82 to 3.98; p < 0.001), progression to acute myelogenous leukemia (HR = 2.59; 95% CI, 1.75 to 3.83; p < 0.001) and platelet count less than 50 g/L at relapse (HR = 1.68; 95% CI, 1.15 to 2.44; p = 0.007). HCT or DLI was an independent factor that favorably impacted OS (HR = 0.40; 95% CI, 0.26 to 0.63; p < 0.001).  

Acute Myelogenous Leukemia
Use of DLI for patients with relapsed acute myelogenous leukemia (AML) after allogeneic HCT has yielded overall remission rates ranging from 15% to 42%, with an OS of 15% to 20%. (For comparison, a second HCT in this group of patients results in 10% to 35% long-term survival, with a treatment-related mortality of approximately 50%.) Patients with lower initial disease burden, reduction in the tumor burden with chemotherapy before DLI and favorable cytogenetics appeared to benefit more with DLI. 

A large retrospective analysis from the European Blood and Marrow Transplant Group compared OS in 399 patients with AML with post-transplant relapse who either were treated with (n = 171) or without (n = 228) DLI.¹² Patients who received DLI had an improved 2-year OS (21%) compared with those who did not (9%; p < 0.001).  

A 2015 large retrospective series from the Center for International Blood and Marrow Transplant Research (CIBMTR) reported outcomes for 1,788 AML patients who experienced a first or second relapsed after allogeneic HCT, among whom 1,231 (69%) received subsequent intensive therapy that included DLI.¹³ Among the 1,231 patients who received treatment, 660 (54%) received chemotherapy alone; 202 (16%) received DLI with or without chemotherapy; and 369 (30%) received a second allogeneic HCT with or without additional chemotherapy or DLI. Among all patients who received DLI, 87 (33%) survived more than 1 year after relapse; median survival was 7 months (range, 1 – 177 months). Cell-based therapy (DLI or second HCT) resulted in significantly better postrelapse OS than chemotherapy alone. These results are consistent with other reports of DLI in patients who had AML relapse after allogeneic HCT.  

The literature for myelodysplasia syndromes (MDS) and other myeloproliferative diseases treated with DLI either after relapse or for mixed chimerism consists of small sample sizes, inconsistent pre-DLI therapy and varied DLI cell doses, making it difficult to draw definite conclusions about outcomes.² However, it appears that some patients attain durable remissions with DLI after post-transplant relapse.²  

Warlick et al. reported CR after DLI in 49% (17/35) patients with relapsed non-CML, including AML and MDS, after allogeneic HCT.¹⁴ OS at 1 year was 30% and 19% at 2 years. The authors reported that a lower dose regimen of DLI was more tolerable and reduced GVHD occurrence to 25% compared with 66% with higher dose DLI.  

An analysis from the German Cooperative Transplant Study Group reported outcomes among a cohort of patients (N = 154) who relapsed after undergoing allogeneic HCT to treat AML (n = 124), MDS (n = 28) or myeloproliferative syndrome (n = 2).¹⁵ All patients received a median of 4 courses of azacitidine, and DLI was administered to 105 (68%). OS among all patients was 29% at 2-year follow-up, which compares favorably with other reports. The overall incidence of acute GVHD based on the total cohort (N = 154) was 23%, and 31% in those given DLI (n = 105).  

Acute Lymphoblastic Leukemia
The graft-versus-tumor effect is thought to be less robust in patients with ALL than in the myeloid leukemias. Smaller studies have reported DLI response rates ranging from 0% to 20% and OS rates of less than 15%.¹ By comparison, a second allogeneic HCT provides a 5-year OS of 15% to 20%, with a treatment-related mortality rate of approximately 50%.¹  

The clinically evident graft-versus-leukemia effect of DLI requires weeks to months to manifest, and, because ALL is a rapidly proliferating disease, DLI only does not control the disease without a significant reduction in leukemia burden before DLI. Management of patients with relapsed ALL leading to the best OS is achieved through a combination of salvage chemotherapy and DLI. Although it is unclear whether DLI adds benefit to salvage chemotherapy, long-term survival has been reported with relapsed ALL treated with chemotherapy plus DLI.²  

Lymphomas
Studies in which patients received DLI for lymphomas consist of small numbers of patients and various histologies (both HL and high- and low-grade NHL). In general, the highest response rates have been seen in the indolent lymphomas. For NHL, too few patients have been reported with any single histologic subtype of lymphoma to provide adequate information on the benefit of DLI for specific subtypes.²  

The largest series reported for NHL (N = 21) using DLI showed response rates in 3 of 9 patients with high-grade NHL, 1 of 2 patients with mantle cell lymphoma and 6 of 10 patients with low-grade disease.¹⁶  

A series of 14 patients with multiply relapsed HL who received reduced-intensity conditioning allogeneic HCT and DLI showed a CR of 57% and 2-year survival of 35%.¹⁷

Multiple Myeloma
Observational data have suggested a graft-versus-tumor effect in multiple myeloma, because the development of GVHD has correlated with response in several analyses.² 

Allogeneic HCT is currently considered experimental for this indication (see evidence review 8.01.17 on HCT for plasma cell dyscrasias including multiple myeloma). Most patients with multiple myeloma who undergo HCT receive an autologous HCT. However, the overall role of HCT for multiple myeloma is changing with the advent of highly active novel agents like lenalidomide and bortezomib.

Five studies (sample size range, 5 – 63 patients) have reported the role of DLI in relapsed multiple myeloma,^{18,19,20,21,22} with the highest response to DLI being reported as 62%, with approximately half of the responders attaining CR.2 One confounding factor for high response rates for multiple myeloma treated with DLI is that corticosteroids used for treating GVHD have a known antimyeloma effect, which could potentially enhance response rates in these patients.¹ 

Section Summary: Donor Lymphocyte Infusion
There are a few nonrandomized comparative studies and numerous case series of DLI treatment for various hematologic malignancies and other myeloproliferative disorders. The nonrandomized studies, in patients with acute leukemia and myelodysplastic syndrome, have reported higher response rates for patients treated with DLI than with alternatives. The case series report higher response rates than expected for relapsed disease compared with historical controls. Although there are no high-quality RCTs for DLI treatment, this evidence permits the conclusion that response rates improve with DLI treatment for patients with previous HCT treatment and relapsed disease.

Modified DLI
In an effort to control GVHD, a group in Italy explored use of genetically modified lymphocytes engineered to express the suicide gene thymidine kinase of herpes simplex virus.²³ These lymphocytes were infused into 23 patients with various hematologic malignancies who relapsed after allogeneic HCT. Six patients died of progressive disease within 4 weeks of infusion. Eleven patients experienced disease response (CR in 6, partial remission in 5). Three patients were still in CR at a median of 471 days. Twelve patients were evaluable for GVHD, 3 of whom developed acute or chronic GVHD, which was successfully treated with ganciclovir.

In a phase 2 trial, donor lymphocytes were treated with rapamycin ex vivo to produce rapamycin-resistant DLIs.²⁴ Forty patients undergoing low-intensity HCT for hematologic malignancy were treated preemptively with chemotherapy and DLI. There were no infusional toxicities or serious events attributable to DLI. Classical acute GVHD occurred in 4 of 40 patients. By the end of the study (follow-up range, 42 – 84 months), 18 of 40 patients remained in sustained remission.

A phase 1 study evaluated patient response to DLI expressing the herpes simplex virus thymidine kinase suicide gene.²⁵ Three patients were enrolled in the trial and received a single DLI. No local or systemic toxicity related to the gene-transfer procedure was observed. Two patients achieved stable disease. No patient had severe GVHD requiring systemic steroid and/or ganciclovir administration. Tyrosine kinase cells were detected in the peripheral blood of all 3 patients by polymerase chain reaction, but did not persist more than 28 days.  

Section Summary: Modified DLI
These early-phase studies are insufficient to determine the efficacy of modified DLI in the treatment of hematologic malignancies. Randomized studies comparing modified DLI to standard treatment would be necessary to determine efficacy.

Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in December 2015 did not identify any ongoing or unpublished trials that would likely influence this review.

Summary of Evidence
For individuals who have had an allogeneic hematopoietic cell transplant (HCT) who receive donor lymphocyte infusion (DLI), the evidence includes nonrandomized comparative studies and case series. Relevant outcomes are overall survival and change in disease status. In various hematologic malignancies and for various indications such as planned or preemptive DLI, treatment of relapse, or conversion of mixed to full donor chimerism, patients have shown evidence of responding to DLI. Response rates to DLI for relapsed hematologic malignancies following an allogeneic HCT are best in chronic myelogenous leukemia (CML), followed by the lymphomas, multiple myeloma and acute leukemias, respectively. Other than CML, clinical responses are most effective when chemotherapy induction is used to reduce the tumor burden before DLI. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

For individuals who have had an allogeneic HCT who receive a modified (genetic or other ex vivo modification) donor lymphocytes infusion, the evidence includes case series. Relevant outcomes are overall survival and change in disease status. The case series have demonstrated the feasibility of the technique and no serious adverse effects. Without a comparison to standard treatment, the efficacy of administering modified donor lymphocytes is unknown. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical Input Received From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, or Blue Distinction Centers for Transplant, unless otherwise noted.

In response to requests, input was received from 1 academic medical center and 5 Blue Distinction Centers for Transplant while this policy was under review in 2011. There was general agreement with the policy statements, although 2 reviewers disagreed with the statement on the use of DLI in nonhematopoietic malignancies; one thought it was investigational and medically necessary and the other did not think this was investigational or medically necessary. One reviewer suggested adding Epstein-Barr virus-associated post-transplant lymphoproliferative disease as a medically necessary indication for DLI. One reviewer commented on an evolving technique for use of ex vivo expansion of donor lymphocytes.

Practice Guidelines and Position Statements
National Comprehensive Cancer Network (NCCN) recommendations for treating CML (v.1.2015) state that DLI can be considered an option for patients who do not achieve remission, are in cytogenetic relapse or have an increasing level of molecular relapse (category 2A).²⁶ 

NCCN guidelines do not address the use of DLI in the treatment of acute myelogenous leukemia (v.1.2015).

NCCN recommendations for treating acute lymphoblastic leukemia (v.2.2014) state that DLI can be considered an option for patients in relapse after allogeneic HCT (category 2A).²⁷ 

NCCN guidelines do not include the use of DLI in the treatment of non-Hodgkin lymphoma or Hodgkin lymphoma (v.2.2015).

NCCN recommendations for treating multiple myeloma (v.4.2015) state that DLI can be considered an option for patients who do not respond or are in relapse after allogeneic HCT (category 2A).²⁸ 

U.S. Preventive Services Task Force Recommendations
Not applicable

References

1. Deol A, Lum LG. Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited. Cancer Treat Rev. Nov 2010;36(7):528-538. PMID 20381970
2. Tomblyn M, Lazarus HM. Donor lymphocyte infusions: the long and winding road: how should it be traveled? Bone Marrow Transplant. Nov 2008;42(9):569-579. PMID 18711351
3. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Technology Assessment 1997; Tab 22.
4. van den Brink MR, Porter DL, Giralt S, et al. Relapse after allogeneic hematopoietic cell therapy. Biol Blood Marrow Transplant. Jan 2010;16(1 Suppl):S138-145. PMID 19857588
5. Simula MP, Marktel S, Fozza C, et al. Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy. Leukemia. May 2007;21(5):943-948. PMID 17361226
6. Dazzi F, Szydlo RM, Cross NC, et al. Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia. Blood. Oct 15 2000;96(8):2712-2716. PMID 11023502
7. Guglielmi C, Arcese W, Dazzi F, et al. Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose. Blood. Jul 15 2002;100(2):397-405. PMID 12091328
8. Fozza C, Szydlo RM, Abdel-Rehim MM, et al. Factors for graft-versus-host disease after donor lymphocyte infusions with an escalating dose regimen: lack of association with cell dose. Br J Haematol. Mar 2007;136(6):833-836. PMID 17341269
9. Radujkovic A, Guglielmi C, Bergantini S, et al. Donor lymphocyte infusions for chronic myeloid leukemia relapsing after allogeneic stem cell transplantation: may we predict graft-versus-leukemia without graft-versus-host disease? Biol Blood Marrow Transplant. Jul 2015;21(7):1230-1236. PMID 25797175
10. El-Jurdi N, Reljic T, Kumar A, et al. Efficacy of adoptive immunotherapy with donor lymphocyte infusion in relapsed lymphoid malignancies. Immunotherapy. May 2013;5(5):457-466. PMID 23638742
11. Guieze R, Damaj G, Pereira B, et al. Management of myelodysplastic syndrome relapsing after allogeneic hematopoietic stem cell transplantation: a study by the French Society of Bone Marrow Transplantation and Cell Therapies. Biol Blood Marrow Transplant. Aug 6 2015. PMID 26256942
12. Schmid C, Labopin M, Nagler A, et al. Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol. Nov 1 2007;25(31):4938-4945. PMID 17909197
13. Bejanyan N, Weisdorf DJ, Logan BR, et al. Survival of patients with acute myeloid leukemia relapsing after allogeneic hematopoietic cell transplantation: a Center for International Blood and Marrow Transplant Research study. Biol Blood Marrow Transplant. Mar 2015;21(3):454-459. PMID 25460355
14. Warlick ED, DeFor T, Blazar BR, et al. Successful remission rates and survival after lymphodepleting chemotherapy and donor lymphocyte infusion for relapsed hematologic malignancies postallogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. Mar 2012;18(3):480-486. PMID 22155141
15. Schroeder T, Rachlis E, Bug G, et al. Treatment of acute myeloid leukemia or myelodysplastic syndrome relapse after allogeneic stem cell transplantation with azacitidine and donor lymphocyte infusions-a retrospective multicenter analysis from the German Cooperative Transplant Study Group. Biol Blood Marrow Transplant. Apr 2015;21(4):653-660. PMID 25540937
16. Morris E, Thomson K, Craddock C, et al. Outcomes after alemtuzumab-containing reduced-intensity allogeneic transplantation regimen for relapsed and refractory non-Hodgkin lymphoma. Blood. Dec 15 2004;104(13):3865-3871. PMID 15304395
17. Peggs KS, Sureda A, Qian W, et al. Reduced-intensity conditioning for allogeneic haematopoietic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: impact of alemtuzumab and donor lymphocyte infusions on long-term outcomes. Br J Haematol. Oct 2007;139(1):70-80. PMID 17854309
18. Lokhorst HM, Schattenberg A, Cornelissen JJ, et al. Donor leukocyte infusions are effective in relapsed multiple myeloma after allogeneic bone marrow transplantation. Blood. Nov 15 1997;90(10):4206-4211. PMID 9354693
19. Salama M, Nevill T, Marcellus D, et al. Donor leukocyte infusions for multiple myeloma. Bone Marrow Transplant. Dec 2000;26(11):1179-1184. PMID 11149728
20. Collins RH, Jr., Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol. Feb 1997;15(2):433-444. PMID 9053463 
21. Bensinger WI, Buckner CD, Anasetti C, et al. Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome. Blood. Oct 1 1996;88(7):2787-2793. PMID 8839877
22. Lokhorst HM, Schattenberg A, Cornelissen JJ, et al. Donor lymphocyte infusions for relapsed multiple myeloma after allogeneic stem-cell transplantation: predictive factors for response and long-term outcome. J Clin Oncol. Aug 2000;18(16):3031-3037. PMID 10944138
23. Ciceri F, Bonini C, Marktel S, et al. Antitumor effects of HSV-TK-engineered donor lymphocytes after allogeneic stem-cell transplantation. Blood. Jun 1 2007;109(11):4698-4707. PMID 17327416
24. Fowler DH, Mossoba ME, Steinberg SM, et al. Phase 2 clinical trial of rapamycin-resistant donor CD4+ Th2/Th1 (T-Rapa) cells after low-intensity allogeneic hematopoietic cell transplantation. Blood. Apr 11 2013;121(15):2864-2874. PMID 23426943
25. Hashimoto H, Kitano S, Ueda R, et al. Infusion of donor lymphocytes expressing the herpes simplex virus thymidine kinase suicide gene for recurrent hematologic malignancies after allogeneic hematopoietic stem cell transplantation. Int J Hematol. Jul 2015;102(1):101-110. PMID 25948083
26. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia. Version 1.2015. http://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed March, 2015.
27. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Acute Lymphoblastic Leukemia. Version 2.2014. http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed March, 2015.
28. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Multiple Myeloma. Version 4.2015. http://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed March, 2015. 

Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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